Acne and seborrhea are conditions of the human skin characterized by the excess flow of sebum (skin oil) from the sebaceous glands. The excess sebum may block or stagnate sebum flow through the hair follicle and thicken therein to form a solid plug known as a comedone. Formation of a comedone stimulates hyperkeratinization of the follicular opening, thus completely closing the duct. The usual result is a papule, a pustule, or a cyst, which becomes contaminated with bacteria such a P-acnes. The resulting infections characterize the disease state known as acne and, in lesser severity, seborrhea.
As described in U.S. Pat. No. 4,056,611, benzoyl peroxide is an antimicrobial agent effective against P-acnes. Salicylic acid is a known keratolytic agent which may be used to remove the horny outer layer of skin composed largely of a substance known as keratin. Salicylic acid also has comedolytic activity, i.e., the ability to dissolve and penetrate comedones, as well as some antimicrobial activity. It is reported in UK patent application GB No. 2018569A that benzoyl peroxide and salicylic acid, when used together at certain specified levels, exhibit a therapeutic effect greater than either agent alone in treating acne.
In solution, benzoyl peroxide and salicylic acid are incompatible with each other because benzoyl peroxide oxidizes salicylic acid, thereby reducing the amounts of both substances. Furthermore, while both benzoyl peroxide and salicylic acid are acceptably non-irritating to the skin, the oxidation products of salicylic acid are unacceptably irritating to the skin. It is desirable to have stable compositions for use as ointments or in toiletries as soaps, detergent bars, skin cleansers, shampoos etc. which contain both benzoyl peroxide and salicylic acid for use against acne.
Although salicylic acid and benzoyl peroxide might be incorporated in two preparations for sequential application, it is difficult to gain consumer acceptance for commercially distributed formulae other than single compositions. The compatibility problems of salicylic acid and benzoyl peroxide may be overcome by incorporating both substances in a composition as dispersed, finely divided particles. Such dispersions are possible in aqueous systems as both benzoyl peroxide and salicylic acid are generally insoluble in water. The above-mentioned UK Application teaches the dispersion of benzoyl peroxide and salicylic acid in aqueous compositions including gelling agents, such as methyl cellulose and thickening agents, such as Veegum K.
Attempts were also described in the above-mentioned UK Application to prepare compositions of benzoyl peroxide and salicylic acid in Carbopol 941. However, these attempts were less than successful, as it was not possible to prepare a uniform stable composition. Carboxy vinyl polymers such as those sold under the registered trademarks Carbopol 941, 940, and 934 of B. F. Goodrich Chemical Co. are recognized as particularly desirable pharmaceutical support vehicles. Carboxy vinyl polymers are generally unaffected by temperature variation within the temperature ranges in which pharmaceutical compositions are stored. They are not subject to hydrolysis or oxidation. Importantly, carboxy vinyl polymers are neither attacked by nor support bacteria or mold growth; however, they do not prevent growth and thus may be used in conjunction with an anti-bacterial and/or anti-fungal agent.
Carboxy vinyl polymers do not cause irritation to skin and produce only minimal irritation and no damage to ocular tissue. Although acne preparations are not intended for internal use, the fact that carboxy vinyl polymers have negligable toxicity (some, e.g., Carbopol 934, have been tested and approved for internal use) assures that inadvertent ingestion will not be harmful. Carboxy vinyl gels, when applied to the skin, rub in well and do not feel greasy or sticky. The gels also provide for ready absorption of the medicament and easy removal by soap and water.
Mucilages or gels of carboxy vinyl polymers are generally formed by dispersing particles of acidic carboxy vinyl polymer with an appropriate base, resulting in the immediate formation of a gel. In the above-mentioned UK Application, the base mentioned for use with Carbopol was diisopropanolamine. The less-than-successful results reported may be attributed to the chemical interaction between the salicylic acid and the basic amine. Stronger bases, e.g., NaOH, if used to gel carboxy vinyl resins, would be expected to result in even more unsatisfactory results.
Because of the demonstrated combined effect of benzoyl peroxide and salicylic acid against acne and seborrhea and the known desirability of carboxy vinyl resins as pharmaceutical supports, it is desirable to have stable dispersions of benzoyl peroxide and salicylic acid in carboxy vinyl polymer gels.